Management of twin reversed arterial perfusion sequence: eight cases over 13 years.

BACKGROUND: Twin reversed arterial perfusion (TRAP) sequence is a rare condition that affects primarily monozygotic monochorionic twin pregnancies in which a normal twin acts as a pump (donor) for an acardiac recipient (perfuse) twin. OBJECTIVE: We report our experience over the last 13 years at a tertiary health care center. DESIGN: Descriptive, retrospective case series SETTING: Tertiary health care center PATIENTS AND METHODS: All TRAP cases managed between the years 2009 and 2022 at our Fetal Diagnosis and Therapy Center were included. Data recorded included demographic and clinical information which was used to generate descriptive data. Patients were managed by a multidisciplinary team with variable interventions. MAIN OUTCOME MEASURE: Survival of normal twin SAMPLE SIZE: Eight RESULTS: Eight pregnant women with TRAP syndrome were managed at our center during that period. One was monozygotic monochorionic and the others were monochorionic diamniotic. Median maternal age at presentation was 27 years and median gestational age at diagnosis was 23 weeks. All were diagnosed with ultrasound (US) imaging. Three were managed with bipolar ligation of the cord of the acardiac twin under general anesthesia, one US-guided (single port) and 2 fetoscopic (2 ports) with a median operative time of 39 minutes. The last five cases were managed with US-guided radiofrequency ablation (RFA) under local anesthesia, one needed 2 sessions, 1 week apart. The median duration of the RFA procedure was 23 minutes. There were no complications and all had viable normal babies born at a median of 32 weeks of gestation (6 C-section, 2 spontaneous membrane rupture). CONCLUSIONS: Acardiac twin cord ligation and RFA are feasible and safe options with excellent outcome for TRAP syndrome. RFA may be preferable owing to its less invasiveness under local anesthesia. LIMITATIONS: None, given the rarity of the disease and the study design. CONFLICT OF INTEREST: None.

Chorioangioma: a single tertiary care center retrospective study.

OBJECTIVES: Chorioangioma represents a challenge due to the rarity of the condition, paucity of sufficient management guidelines, and controversies regarding the best invasive fetal therapy option; most of the scientific evidence for clinical treatment has been limited to case reports. The aim of this retrospective study was to review the natural antenatal history, maternal and fetal complications, and therapeutic modalities used in pregnancies complicated with placental chorioangioma at a single Center. METHODS: This retrospective study was conducted at King Faisal Specialist Hospital and Research Center (KFSH&RC) in Riyadh, Saudi Arabia. Our study population included all pregnancies with ultrasound features of chorioangioma, or histologically confirmed chorioangiomas, between January 2010 and December 2019. Data were collected from the patients' medical records, including the ultrasound reports and histopathology results. All subjects were kept anonymous; case numbers were used as identifiers. Data collected by the investigators were entered into Excel worksheets in an encrypted format. A MEDLINE database was used to retrieve 32 articles for literature review. RESULTS: Over a 10-year period between January 2010 and December 2019, 11 cases of chorioangioma were identified. Ultrasound remains the gold standard for diagnosis and follow-up of the pregnancy. Seven of the 11 cases were detected by ultrasound, allowing proper fetal surveillance and antenatal follow-up. Of the remaining six patients, one underwent radiofrequency ablation, two underwent intrauterine transfusion for fetal anemia due to placenta chorioangioma, one had vascular embolization with an adhesive material, and two were managed conservatively until term with ultrasound surveillance. CONCLUSIONS: Ultrasound remains the gold standard modality for prenatal diagnosis and follow-up of pregnancies with suspected chorioangiomas. Tumor size and vascularity play a significant role in the development of maternal-fetal complications and the success of fetal interventions. To determine the superior modality of fetal intervention mandates more data and research; nevertheless, Fetoscopic Laser Photocoagulation and embolization with adhesive material seem to be a lead choice, with reasonable fetal survival.

Observational cohort study of perinatal outcomes of women with COVID-19.

BACKGROUND: Understanding the impact of SARS-CoV-2 infection on pregnancy outcomes and of pregnancy on COVID-19 outcomes is critical for ensuring proper prenatal and antenatal care. No similar studies have been published in Saudi Arabia. METHODS: We performed a prospective cohort study of pregnant women with confirmed SARS-CoV-2 infection who presented at King Faisal Specialist Hospital and Research Center (KFSHRC) in Riyadh, Kingdom of Saudi Arabia. COVID-19 staging was performed, pregnancy-related complications were assessed, and neonatal infection was evaluated. RESULTS: We enrolled 81 patients (mean age 31.75 years, SD 5.25) of which there were 17 cases in the first trimester, 20 in the second trimester, and 34 in the third trimester. The distribution of COVID-19 severity was 40 patients with Stage A, 36 with Stage B, 4 with Stage C, and 1 with Stage D. Complications were pregnancy loss in 2 patients (one in each first and second trimester) and 1 fetal death after 20 weeks of pregnancy, 7 patients with fetal growth restriction, and 8 with pre-term delivery. CONCLUSIONS: We did not observe an unusual frequency of pregnancy-related complications due to SARS-CoV-2 infection in this high-risk obstetric population and there was no evidence of vertical transmission in newborns from women who delivered while positive for the virus.

Efficacy of hyoscine in pain management during hysteroscopy: a systematic review and meta-analysis

We conducted a systematic review and meta-analysis of relevant clinical trials from full-text, scientific journal archives to assess the efficacy of hyoscine for the management of pain during in-office hysteroscopy (OH) procedures. Cochrane CENTRAL, ClinicalTrials.Gov, MEDLINE, PubMed, SCOPUS and the Web of Science were searched for all clinical trials that matched our search criteria. A full assessment of bias was made using the Cochrane Group tool-set. The following outcomes were included: visual analogue scale (VAS) score for postoperative pain, postoperative need for analgesia, and procedure time. In the case of homogeneous data, the analysis was performed using a fixed effects system, and the random effects system was used with heterogeneous data. Inclusion criteria included only randomized clinical trials, and interventions that included patients receiving hyoscine-N-Butyl Bromide during OH, regardless of dose or mode of administration, and compared this with placebo. Three clinical trials were included. The actual mean difference (MD) of the VAS pain score showed no significant difference between hyoscine or placebo [MD: -0.28 (-1.08, 0.52), (p=0.49)]. For postoperative analgesia, the overall MD showed no significant difference between hyoscine or placebo [MD: 0.43 (0.16, 1.14), (p=0.09)]. For procedure time, the combined effect estimate failed to show any significant difference between hyoscine and placebo [MD: -0.66 (-2.77, 1.44) (p=0.54)]. Contrary to previously published data, our meta-analysis using the latest available RCTs fails to show hyoscine as being effective in reducing pain or the need for other forms of anesthesia in OH.

The effect of hyoscine-N-butylbromide on pain perception during and after hysterosalpingography in infertile women: a systematic review and meta-analysis of randomised controlled trials.

This paper reports a systematic review and meta-analysis of the effectiveness of hyoscine-N-butylbromide (HBB) administration in hysterosalpingography (HSG). Four electronic databases were searched for randomised controlled trials (RCTs) that compared HBB versus placebo or no intervention in infertile women undergoing HSG. Pain during and after HSG and different adverse events including nausea, vomiting, and dizziness were evaluated. Three RCTs with 335 patients were included. The analysis showed HBB was significantly effective in reducing pain during and after HSG (MD = -0.76 mm, 95% CI [-1.35, -0.17], p = 0.01) and (MD = -0.81 mm, 95% CI [-1.07, -0.56], p < 0.001), respectively. There were no significant differences in adverse events between HBB and control groups. The methodological evidence quality was high as evaluated by GRADEpro. In conclusion, this review provides good evidence that prior administration of HBB is effective in reducing induced pain during and after HSG with tolerable side effects.

Prenatal exome sequencing and chromosomal microarray analysis in fetal structural anomalies in a highly consanguineous population reveals a propensity of ciliopathy genes causing multisystem phenotypes.

Fetal abnormalities are detected in 3% of all pregnancies and are responsible for approximately 20% of all perinatal deaths. Chromosomal microarray analysis (CMA) and exome sequencing (ES) are widely used in prenatal settings for molecular genetic diagnostics with variable diagnostic yields. In this study, we aimed to determine the diagnostic yield of trio-ES in detecting the cause of fetal abnormalities within a highly consanguineous population. In families with a history of congenital anomalies, a total of 119 fetuses with structural anomalies were recruited and DNA from invasive samples were used together with parental DNA samples for trio-ES and CMA. Data were analysed to determine possible underlying genetic disorders associated with observed fetal phenotypes. The cohort had a known consanguinity of 81%. Trio-ES led to diagnostic molecular genetic findings in 59 fetuses (with pathogenic/likely pathogenic variants) most with multisystem or renal abnormalities. CMA detected chromosomal abnormalities compatible with the fetal phenotype in another 7 cases. Monogenic ciliopathy disorders with an autosomal recessive inheritance were the predominant cause of multisystem fetal anomalies (24/59 cases, 40.7%) with loss of function variants representing the vast majority of molecular genetic abnormalities. Heterozygous de novo pathogenic variants were found in four fetuses. A total of 23 novel variants predicted to be associated with the phenotype were detected. Prenatal trio-ES and CMA detected likely causative molecular genetic defects in a total of 55% of families with fetal anomalies confirming the diagnostic utility of trio-ES and CMA as first-line genetic test in the prenatal diagnosis of multisystem fetal anomalies including ciliopathy syndromes.

Complications of intravascular intrauterine transfusion for Rh alloimmunization.

BACKGROUND: Intravascular intrauterine transfusion (IUT) is considered a safe procedure, but complications still occur, including fatalities. OBJECTIVE: Review the outcomes of Rh alloimmunization, including indications and possible complications. DESIGN: Retrospective cohort (medical record review). SETTING: Tertiary care center. PATIENTS AND METHODS: We retrieved the records for all mothers who had an IUT for Rh alloimmunization between January 2009 and August 2019. We collected data on complications, post-transfusion hemoglobin and antibody combinations. MAIN OUTCOME MEASURE: Complications of IUT. SAMPLE SIZE: 119 mothers with 154 fetuses (154 different pregnancies). RESULTS: The 154 fetuses had 560 intrauterine transfusions. The median pre-IUT hemoglobin was a median of 8.0 g/dL while the median post-IUT hemoglobin 16 g/dL. Immediate procedure-related complications included fetal bradycardia in 2.7%, significant bleeding from the cord puncture site (for more than 2 minutes in 0.9%), and contractions in 0.9%. Eight (5.2%) were delivered by cesarean delivery due to IUT-specific complications such as post-procedure fetal bradycardia. Intrauterine fetal death complicated 8.4% of the pregnancies (13 fetuses). Phototherapy was required in 76 (49.4%), postnatal blood transfusions in 17 (11%), and exchange transfusion in 11 (7.1%). Neonatal death occurred 8 (5.2%). Data were insufficient to assess associations of complications with antibody combinations. CONCLUSIONS: Intrauterine transfusion is an effective treatment with high survival rates (around 90% for cases of Rh alloimmunization). LIMITATIONS: Case series. CONFLICT OF INTEREST: None.

Knowledge and attitudes regarding non-invasive prenatal testing among women in Saudi Arabia.

OBJECTIVES: To explore women's knowledge and attitudes regarding NIPT, its implications, the factors affecting their decision to undergo the test and actions taken following a positive result. METHODS: In this descriptive study, women who were offered NIPT through the foetal maternal clinic, were asked to complete an anonymous questionnaire about NIPT. The questionnaire consisted of 29 statements and covered four areas: demographics, knowledge, attitudes and decision-making. RESULTS: A total of 150 women who were offered NIPT participated in this study. The results showed that generally women had poor knowledge of critical aspects of NIPT. This included the conditions tested for, the implications of the test and its limitations. Over 90% of women were in favour of NIPT and it being offered to all women of advanced maternal age while 66% of the tested women agreed to having confirmatory invasive testing in the case of a positive result. CONCLUSION: This study shows that the acceptance rate for NIPT is high despite incomplete understanding of the benefits and limitations of the test. The study findings support the need for education regarding this test through dedicated genetic counselling sessions in order to ensure that an informed decision can be made.

Novel loss of function variants in FRAS1 AND FREM2 underlie renal agenesis in consanguineous families.

INTRODUCTION: Congenital anomalies of the kidney and urinary tract (CAKUT) are a group of abnormalities that affect structure of the kidneys or other structures of the urinary tract. The majority of CAKUT are asymptomatic and are diagnosed prenatally by ultrasound scanning or found incidentally in postnatal life. CAKUT varies in severity and may lead to life-threatening kidney failure and end-stage kidney disease. Renal agenesis, a severe form of CAKUT, is a congenital absence of one or both kidneys. Bilateral renal agenesis belongs to a group of prenatally lethal renal diseases and is often detected on fetal ultrasound scanning during the investigation of oligohydramnios. Approximately 40% of fetuses with bilateral renal agenesis are stillborn or die a few hours postnatally. Mutations in many renal development genes have been shown to be associated with renal agenesis. METHODS: Six consanguineous Saudi Arabian families were recruited to study the molecular genetic causes of recurrent miscarriages and lost fetuses due to oligohydramnios, renal agenesis and other congenital anomalies. Whole exome sequencing was employed to underlying detect genetic defects. RESULTS: Novel loss of function variants were detected in FRAS1 and FREM2. In FRAS1, a homozygous splice site variant c.9780+2T>C was found in an affected fetus, segregating form each parent. In addition, in three other families both parents were heterozygous for a frameshift variant (c.8981dupT; p.His2995Profs*3) and splice site variants (c.5217+1G>C and c.8098+2T>A), respectively. In FREM2, a homozygous nonsense variant (c.2303C>G; p.Ser768*) was found in an affected fetus, segregating from both parents. In another family, both parents carried a FREM2 heterozygous frameshift variant (c.3969delC; p.Asn1323Lysfs*5). CONCLUSION: We describe consanguineous families with clinical features of antenatal oligohydramnios and bilateral renal agenesis, in whom we have identified novel pathogenic variants in FRAS1 and FREM2. These finding highlights the association between mutations in FRAS1 and FREM2 and antenatal/perinatal death.

Variants in LSM7 impair LSM complexes assembly, neurodevelopment in zebrafish and may be associated with an ultra-rare neurological disease.

Leukodystrophies, genetic neurodevelopmental and/or neurodegenerative disorders of cerebral white matter, result from impaired myelin homeostasis and metabolism. Numerous genes have been implicated in these heterogeneous disorders; however, many individuals remain without a molecular diagnosis. Using whole-exome sequencing, biallelic variants in LSM7 were uncovered in two unrelated individuals, one with a leukodystrophy and the other who died in utero. LSM7 is part of the two principle LSM protein complexes in eukaryotes, namely LSM1-7 and LSM2-8. Here, we investigate the molecular and functional outcomes of these LSM7 biallelic variants in vitro and in vivo. Affinity purification-mass spectrometry of the LSM7 variants showed defects in the assembly of both LSM complexes. Lsm7 knockdown in zebrafish led to central nervous system defects, including impaired oligodendrocyte development and motor behavior. Our findings demonstrate that variants in LSM7 cause misassembly of the LSM complexes, impair neurodevelopment of the zebrafish, and may be implicated in human disease. The identification of more affected individuals is needed before the molecular mechanisms of mRNA decay and splicing regulation are added to the categories of biological dysfunctions implicated in leukodystrophies, neurodevelopmental and/or neurodegenerative diseases.

Bleeding and thrombotic risk in pregnant women with Fontan physiology.

BACKGROUND/OBJECTIVES: Pregnancy may potentiate the inherent hypercoagulability of the Fontan circulation, thereby amplifying adverse events. This study sought to evaluate thrombosis and bleeding risk in pregnant women with a Fontan. METHODS: We performed a retrospective observational cohort study across 13 international centres and recorded data on thrombotic and bleeding events, antithrombotic therapies and pre-pregnancy thrombotic risk factors. RESULTS: We analysed 84 women with Fontan physiology undergoing 108 pregnancies, average gestation 33±5 weeks. The most common antithrombotic therapy in pregnancy was aspirin (ASA, 47 pregnancies (43.5%)). Heparin (unfractionated (UFH) or low molecular weight (LMWH)) was prescribed in 32 pregnancies (30%) and vitamin K antagonist (VKA) in 10 pregnancies (9%). Three pregnancies were complicated by thrombotic events (2.8%). Thirty-eight pregnancies (35%) were complicated by bleeding, of which 5 (13%) were severe. Most bleeds were obstetric, occurring antepartum (45%) and postpartum (42%). The use of therapeutic heparin (OR 15.6, 95% CI 1.88 to 129, p=0.006), VKA (OR 11.7, 95% CI 1.06 to 130, p=0.032) or any combination of anticoagulation medication (OR 13.0, 95% CI 1.13 to 150, p=0.032) were significantly associated with bleeding events, while ASA (OR 5.41, 95% CI 0.73 to 40.4, p=0.067) and prophylactic heparin were not (OR 4.68, 95% CI 0.488 to 44.9, p=0.096). CONCLUSIONS: Current antithrombotic strategies appear effective at attenuating thrombotic risk in pregnant women with a Fontan. However, this comes with high (>30%) bleeding risk, of which 13% are life threatening. Achieving haemostatic balance is challenging in pregnant women with a Fontan, necessitating individualised risk-adjusted counselling and therapeutic approaches that are monitored during the course of pregnancy.

Fetal Anomalies Associated with Novel Pathogenic Variants in TMEM94.

BACKGROUND: Intellectual developmental disorder with cardiac defects and dysmorphic facies (IDDCDF, MIM 618316) is a newly described disorder. It is characterized by global developmental delay, intellectual disability and speech delay, congenital cardiac malformations, and dysmorphic facial features. Biallelic pathogenic variants of TMEM94 are associated with IDDCDF. METHODS AND RESULTS: In a prenatal setting, where fetal abnormalities were detected using antenatal sonography, we used trio-exome sequencing (trio-ES) in conjunction with chromosomal microarray analysis (CMA) to identify two novel homozygous loss of function variants in the TMEM94 gene (c.606dupG and c.2729-2A>G) in two unrelated Saudi Arabian families. CONCLUSIONS: This study provides confirmation that TMEM94 variants may cause IDDCDF. For the first time we describe the pathogenicity of TMEM94 defects detected during the prenatal period.

Absence of GP130 cytokine receptor signaling causes extended Stüve-Wiedemann syndrome.

The gene IL6ST encodes GP130, the common signal transducer of the IL-6 cytokine family consisting of 10 cytokines. Previous studies have identified cytokine-selective IL6ST defects that preserve LIF signaling. We describe three unrelated families with at least five affected individuals who presented with lethal Stüve-Wiedemann-like syndrome characterized by skeletal dysplasia and neonatal lung dysfunction with additional features such as congenital thrombocytopenia, eczematoid dermatitis, renal abnormalities, and defective acute-phase response. We identified essential loss-of-function variants in IL6ST (a homozygous nonsense variant and a homozygous intronic splice variant with exon skipping). Functional tests showed absent cellular responses to GP130-dependent cytokines including IL-6, IL-11, IL-27, oncostatin M (OSM), and leukemia inhibitory factor (LIF). Genetic reconstitution of GP130 by lentiviral transduction in patient-derived cells reversed the signaling defect. This study identifies a new genetic syndrome caused by the complete lack of signaling of a whole family of GP130-dependent cytokines in humans and highlights the importance of the LIF signaling pathway in pre- and perinatal development.

Bialleleic PKD1 mutations underlie early-onset autosomal dominant polycystic kidney disease in Saudi Arabian families.

BACKGROUND: Polycystic kidney disease (PKD) is one of the most common genetic renal diseases and may be inherited in an autosomal dominant or autosomal recessive pattern. Pathogenic variants in two major genes, PKD1 and PKD2, and two rarer genes, GANAB and DNAJB11, cause autosomal dominant PKD (ADPKD). Early onset and severe PKD can occur with PKD1 and PKD2 pathogenic variants and such phenotypes may be modified by second alleles inherited in trans. Homozygous or compound heterozygous hypomorphic PKD1 variants may also cause a moderate to severe disease PKD phenotype. METHODS: Targeted renal gene panel followed by Sanger sequencing of PKD1 gene were employed to investigate molecular causes in early onset PKD patients. RESULTS: In this study, we report four consanguineous Saudi Arabian families with early onset PKD which were associated with biallelic variants in PKD1 gene. CONCLUSIONS: Our findings confirm that PKD1 alleles may combine to produce severe paediatric onset PKD mimicking the more severe autosomal recessive ciliopathy syndromes associated with PKD. Screening of parents of such children may also reveal subclinical PKD phenotypes.

Lessons Learned from Large-Scale, First-Tier Clinical Exome Sequencing in a Highly Consanguineous Population.

We report the results of clinical exome sequencing (CES) on >2,200 previously unpublished Saudi families as a first-tier test. The predominance of autosomal-recessive causes allowed us to make several key observations. We highlight 155 genes that we propose to be recessive, disease-related candidates. We report additional mutational events in 64 previously reported candidates (40 recessive), and these events support their candidacy. We report recessive forms of genes that were previously associated only with dominant disorders and that have phenotypes ranging from consistent with to conspicuously distinct from the known dominant phenotypes. We also report homozygous loss-of-function events that can inform the genetics of complex diseases. We were also able to deduce the likely causal variant in most couples who presented after the loss of one or more children, but we lack samples from those children. Although a similar pattern of mostly recessive causes was observed in the prenatal setting, the higher proportion of loss-of-function events in these cases was notable. The allelic series presented by the wealth of recessive variants greatly expanded the phenotypic expression of the respective genes. We also make important observations about dominant disorders; these observations include the pattern of de novo variants, the identification of 74 candidate dominant, disease-related genes, and the potential confirmation of 21 previously reported candidates. Finally, we describe the influence of a predominantly autosomal-recessive landscape on the clinical utility of rapid sequencing (Flash Exome). Our cohort's genotypic and phenotypic data represent a unique resource that can contribute to improved variant interpretation through data sharing.

Autozygome and high throughput confirmation of disease genes candidacy.

PURPOSE: Establishing links between Mendelian phenotypes and genes enables the proper interpretation of variants therein. Autozygome, a rich source of homozygous variants, has been successfully utilized for the high throughput identification of novel autosomal recessive disease genes. Here, we highlight the utility of the autozygome for the high throughput confirmation of previously published tentative links to diseases. METHODS: Autozygome and exome analysis of patients with suspected Mendelian phenotypes. All variants were classified according to the American College of Medical Genetics and Genomics guidelines. RESULTS: We highlight 30 published candidate genes (ACTL6B, ADAM22, AGTPBP1, APC, C12orf4, C3orf17 (NEPRO), CENPF, CNPY3, COL27A1, DMBX1, FUT8, GOLGA2, KIAA0556, LENG8, MCIDAS, MTMR9, MYH11, QRSL1, RUBCN, SLC25A42, SLC9A1, TBXT, TFG, THUMPD1, TRAF3IP2, UFC1, UFM1, WDR81, XRCC2, ZAK) in which we identified homozygous likely deleterious variants in patients with compatible phenotypes. We also identified homozygous likely deleterious variants in 18 published candidate genes (ABCA2, ARL6IP1, ATP8A2, CDK9, CNKSR1, DGAT1, DMXL2, GEMIN4, HCN2, HCRT, MYO9A, PARS2, PLOD3, PREPL, SCLT1, STX3, TXNRD2, WIPI2) although the associated phenotypes are sufficiently different from the original reports that they represent phenotypic expansion or potentially distinct allelic disorders. CONCLUSIONS: Our results should facilitate the timely relabeling of these candidate disease genes in relevant databases to improve the yield of clinical genomic sequencing.

The many faces of peroxisomal disorders: Lessons from a large Arab cohort.

Defects in the peroxisomes biogenesis and/or function result in peroxisomal disorders. In this study, we describe the largest Arab cohort to date (72 families) of clinically, biochemically and molecularly characterized patients with peroxisomal disorders. At the molecular level, we identified 43 disease-causing variants, half of which are novel. The founder nature of many of the variants allowed us to calculate the minimum disease burden for these disorders in our population ~1:30 000, which is much higher than previous estimates in other populations. Clinically, we found an interesting trend toward genotype/phenotype correlation in terms of long-term survival. Nearly half (40/75) of our peroxisomal disorders patients had documented survival beyond 1 year of age. Most unusual among the long-term survivors was a multiplex family in which the affected members presented as adults with non-specific intellectual disability and epilepsy. Other unusual presentations included the very recently described peroxisomal fatty acyl-CoA reductase 1 disorder as well as CRD, spastic paraparesis, white matter (CRSPW) syndrome. We conclude that peroxisomal disorders are highly heterogeneous in their clinical presentation. Our data also confirm the demonstration that milder forms of Zellweger spectrum disorders cannot be ruled out by the "gold standard" very long chain fatty acids assay, which highlights the value of a genomics-first approach in these cases.

KIAA1109 Variants Are Associated with a Severe Disorder of Brain Development and Arthrogryposis.

Whole-exome and targeted sequencing of 13 individuals from 10 unrelated families with overlapping clinical manifestations identified loss-of-function and missense variants in KIAA1109 allowing delineation of an autosomal-recessive multi-system syndrome, which we suggest to name Alkuraya-Kucinskas syndrome (MIM 617822). Shared phenotypic features representing the cardinal characteristics of this syndrome combine brain atrophy with clubfoot and arthrogryposis. Affected individuals present with cerebral parenchymal underdevelopment, ranging from major cerebral parenchymal thinning with lissencephalic aspect to moderate parenchymal rarefaction, severe to mild ventriculomegaly, cerebellar hypoplasia with brainstem dysgenesis, and cardiac and ophthalmologic anomalies, such as microphthalmia and cataract. Severe loss-of-function cases were incompatible with life, whereas those individuals with milder missense variants presented with severe global developmental delay, syndactyly of 2nd and 3rd toes, and severe muscle hypotonia resulting in incapacity to stand without support. Consistent with a causative role for KIAA1109 loss-of-function/hypomorphic variants in this syndrome, knockdowns of the zebrafish orthologous gene resulted in embryos with hydrocephaly and abnormally curved notochords and overall body shape, whereas published knockouts of the fruit fly and mouse orthologous genes resulted in lethality or severe neurological defects reminiscent of the probands' features.

Corrigendum: Autozygosity reveals recessive mutations and novel mechanisms in dominant genes: implications in variant interpretation.

This corrects the article DOI: 10.1038/gim.2017.22.